[go: up one dir, main page]

US10314914B2 - Iodophor composition and methods of use - Google Patents

Iodophor composition and methods of use Download PDF

Info

Publication number
US10314914B2
US10314914B2 US15/544,222 US201615544222A US10314914B2 US 10314914 B2 US10314914 B2 US 10314914B2 US 201615544222 A US201615544222 A US 201615544222A US 10314914 B2 US10314914 B2 US 10314914B2
Authority
US
United States
Prior art keywords
dmso
pvp
composition
patient
infection
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US15/544,222
Other languages
English (en)
Other versions
US20180008715A1 (en
Inventor
Joseph Capriotti
Kara Capriotti
Jesse Pelletier
Kevin Stewart
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Veloce Biopharma LLC
Original Assignee
Veloce Biopharma LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Veloce Biopharma LLC filed Critical Veloce Biopharma LLC
Priority to US15/544,222 priority Critical patent/US10314914B2/en
Assigned to VELOCE BIOPHARMA, LLC reassignment VELOCE BIOPHARMA, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CAPRIOTTI, Joseph
Assigned to VELOCE BIOPHARMA, LLC reassignment VELOCE BIOPHARMA, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CAPRIOTTI, Kara
Assigned to VELOCE BIOPHARMA, LLC reassignment VELOCE BIOPHARMA, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PELLETIER, Jesse
Assigned to VELOCE BIOPHARMA, LLC reassignment VELOCE BIOPHARMA, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STEWART, KEVIN
Publication of US20180008715A1 publication Critical patent/US20180008715A1/en
Application granted granted Critical
Publication of US10314914B2 publication Critical patent/US10314914B2/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A61K31/79—Polymers of vinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides

Definitions

  • Verruca vulgaris the medical term for wart, can arise anywhere on the body and serves as an umbrella term for all warts. Warts can result from viral infections that are most often associated with Human Papilloma Virus (HPV) or Molluscum Contagiosum Virus (MCV).
  • HPV Human Papilloma Virus
  • MMV Molluscum Contagiosum Virus
  • HPV Human papilloma viruses
  • Genital infection with HPV can result from intimate contact with individuals harboring clinical or subclinical HPV infection, and is one of the most common sexually transmitted diseases among adolescents and adults. Prevalence of HPV infection in the adult population differs depending upon geographical location, but typically ranges from 20% to 45% of all populations. In the US, 20 million people have genital HPV infection at any given time, amounting to an annual cost burden of $6 billion per year in healthcare dollars spent for sexually transmitted infections (second only to HIV).
  • Non-genital viral infections of the skin may occur via direct person-to-person skin contact, or indirectly through contaminated surfaces in a publicly accessed area, such as a public swimming pool or gymnasium.
  • the skin is exposed to the virus through minor abrasions and infection is promoted via maceration of the epithelia. Autoinoculation is common as well.
  • Non-genital varieties of skin warts occur in 20% of schoolchildren with equal frequency in both sexes.
  • Verruca palmares et plantares are thick, endophytic papules and plaques with numerous thrombosed capillaries that often coalesce into large dome-like elevations. They are often painful due to deep inward growth and are notoriously difficult to eradicate. HPV-1, 2, 27 and 57 are the most common culprits of palm or sole warts.
  • Verrucae plana flat warts are skin-colored or pink, smooth-surfaced, slightly elevated and flat-topped papules most commonly located on the dorsal hands, legs, or face. They are often in a linear array as scratching or shaving can spread them. HPV types 3 and 10 cause this phenotype.
  • Condyloma acuminata (genital warts) are found on the external genitalia and perineum, perianal, or in adjacent areas such as the inguinal folds or mons pubis. They can range in size from a few millimeters to centimeters and are most commonly sessile, smooth-surfaced exophytic papillomas that can be skin colored, brown or white. They lack the thick hyperkeratotic layer of common warts found on skin. HPV-6 and 11 cause genital warts in the majority of cases.
  • Blepharitis is a commonly encountered condition affecting approximately 15% of the population, and represents an inflammatory condition of the eyelids. Blepharitis may involve the dermis, eyelashes, tarsal conjunctiva, mucocutaneous junction or meibomian glands and is most often caused by gram positive bacterial infection, such as Stapylococcus, Corynebacterium , and Pripionibacterium species. However, other agents causing blepharitis include viral, demodex (mite), or yeast infections, seborrhea, rosacea, and hormonal dysregulation.
  • blepharitis may cause dry eye exacerbation, loss of cilia, corneal ulceration, and impart increased risk of endophthalmitis after cataract surgery.
  • it is commonly compartmentalized into inflammation affecting the structures of the anterior, posterior lid margin or both.
  • Anterior blepharitis most commonly presents as anterior lid and lash crusting with or without the presence of collarettes.
  • Other manifesations may also include skin or lash flaking associated with seborrhea or angular inflammation particular to Moraxella or virus.
  • Posterior blepharitis is also commonly referred to as meibomian gland disease.
  • Meibomian glands are responsible for the release of lipids into the tear film, effectively mitigating evaporative tear loss.
  • the posterior variant may further be characterized by inspissation of the meibomian glands, keratinization of orifices, telangiectasia, and posterior margin lid thickening.
  • Bacterial lipases stemming from the ocular flora may also act upon meibomian secretions creating free fatty acids which further disturb the ocular surface.
  • compositions comprising an iodophor, such as povidone-iodine (PVP-I) as an active ingredient, and dimethyl sulfoxide (DMSO) used as a penetration enhancer for the active ingredient.
  • PVP-I povidone-iodine
  • DMSO dimethyl sulfoxide
  • PVP-I is a well-known antiseptic with a broad spectrum of activity against viral, fungal, and bacterial species, as well as demodex, and has no known bacterial, fungal or viral resistance.
  • PVP-I has also been shown to inhibit the formation of biofilms and to eliminate biofilms that have already formed.
  • DMSO dimethyl sulfoxide
  • DMSO enhances penetration for small molecules or low molecular weight (LMW) compounds or drugs, but does not enhance penetration of high molecular weight (HMW) compounds greater than about 10,000 Daltons, such as polymers.
  • LMW low molecular weight
  • HMW high molecular weight
  • DMSO povidone-iodine
  • PVP-I preparations range in molecular weights from 1,000 to 1,000,000 or more.
  • Topical pharmaceutical compositions have been approved using only PVP grades K29-32.
  • PVP K30 One acceptable PVP grade is PVP K30, which has a MW of 30,000 to 60,000 daltons (average MW of about 40,000 daltons). Accordingly, prior to the teachings of Capriotti '559, one skilled in the art would not employ DMSO in a topical pharmaceutical composition to enhance skin penetration of large molecules, polymers or high-molecular weight substances such as PVP-I.
  • topical gel formulations comprising an iodophor, such as PVP-I, in DMSO were particularly useful in treating certain viral, demodex, fungal/yeast, or bacterial infections manifesting as skin infections (e.g., warts) or ophthalmic conditions (e.g., blepharitis).
  • the current invention is a significant advance to the art, and discloses the surprising and unexpected discovery that a topical gel composition comprising an iodophor such as PVP-I, DMSO, and a gelling agent can provide advantageous and unexpected results in the treatment of warts or other skin infections, including skin infection of the eye such as blepharitis.
  • the present invention concerns a topical gel composition
  • a topical gel composition comprising an iodophor, a penetration enhancer, and a gelling agent, wherein the composition is particularly effective in treating viral, demodex, fungal/yeast, or bacterial infection that can cause warts or blepharitis.
  • the subject invention further comprises a method of treating viral, demodex, fungal/yeast, or bacterial infection using a topical gel composition as disclosed herein.
  • the composition can further comprise optional pharmaceutically acceptable excipients or solvents or co-solvents.
  • a composition of the subject invention preferably comprises active pharmaceutical ingredient (API) recognized as appropriate and acceptable for use in a pharmaceutical preparation by the United States Food and Drug Administration (FDA).
  • a preferred composition of the invention further comprises inactive ingredients or excipients recognized as appropriate and acceptable for use in a pharmaceutical preparation for topical administration.
  • An FDA-approved API or acceptable inactive ingredient or excipient is referred to herein as “pharmaceutically acceptable.”
  • a topical composition, formulation, or preparation of the subject invention comprising a pharmaceutically acceptable API, inactive ingredient or excipient is referred to herein as a “pharmaceutically acceptable” topical composition.
  • an ophthalmic composition of the subject invention comprising FDA-approved active or inactive ingredients acceptable for use in an ophthalmic preparation
  • a pharmaceutically acceptable ophthalmic composition or “ophthalmically acceptable” composition, comprising API, excipient, or solvent which is “pharmaceutically acceptable” for ophthalmic use, or is “ophthalmically acceptable.”
  • the subject invention relates, in a preferred embodiment, to a stable topical composition
  • a stable topical composition comprising an iodophor having a molecular weight of greater than 10,000 Daltons, dimethyl sulfoxide (DMSO), and a gelling agent, and optional additional pharmaceutically or ophthalmically acceptable excipients or solvents or co-solvents.
  • DMSO dimethyl sulfoxide
  • a composition of the subject invention can be useful in a method for treating viral infection or viral wart infection, demodex infection, fungal or yeast infection, or bacterial infection of the skin, hair follicle, or genitalia, and can further be useful for treating blepharitis, which can be caused by viral wart infection, demodex infection, fungal or yeast infection, or bacterial infection of the eyelids, conjunctiva, cornea, ocular surface or Meibomian glands.
  • a topical gel composition of the subject invention is unexpectedly highly stable at room temperature in the presence of aqueous or anhydrous ingredients.
  • a topical gel composition of the subject invention comprises about 0.1% to about 10% povidone-iodine (PVP-I); about 30% to about 99% dimethyl sulfoxide (DMSO); and about 1% to about 10% gelling agent.
  • PVP-I povidone-iodine
  • DMSO dimethyl sulfoxide
  • the topical gel composition of the invention unexpectedly exhibits greater efficacy in treating skin infection or blepharitis, compared to a liquid composition substantially free of a gelling agent and comprising about 0.1% to about 10% povidone-iodine and about 30% to about 99% DMSO.
  • a preferred composition comprises about 1% to about 5% PVP-I.
  • a more preferred composition can comprise about 1% PVP-I or about 2% PVP-I.
  • a PVP-I employing povidone grade of K30 is preferred for use in the subject composition.
  • a preferred composition comprises about 30% to about 70% DMSO.
  • a more preferred composition can comprise about 40% to about 49% DMSO, and even more preferably, about 44% DMSO.
  • a preferred composition comprises about 2% to about 5% gelling agent.
  • a more preferred composition can comprise about 4% gelling agent.
  • a particularly useful composition which has been prepared for testing comprises 2% PVP-I; 44% DMSO; 4% hydroxyethylcellulose, and 50% aqueous solvent.
  • a preferred aqueous solvent is water or isotonic buffer.
  • a composition of the invention can include a gelling agent, as is well known in the art, which can be selected from a gum, agar, carrageenan, petrolatum, or a cellulosic polymer or the like.
  • a gelling agent as is well known in the art, which can be selected from a gum, agar, carrageenan, petrolatum, or a cellulosic polymer or the like.
  • One preferred cellulosic polymer as a gelling agent is hydroxyethyl cellulose.
  • An alternative cellulosic polymer gelling agent is hydroxymethyl cellulose.
  • a composition of the invention preferably comprises povidone-iodine, or PVP-I having an average molecular weight greater than 10,000. More preferably, the composition of the invention comprises PVP-I having an average molecular weight between about 20,000 to about 1,000,000. One preferred embodiment comprises PVP-I having an average molecular weight between about 30,000 to about 60,000, or greater. Each of the PVP-I ingredients is referred to herein as a “high molecular weight PVP-I,” or “HMW PVP-I.”
  • compositions according to the subject invention are stable, topical ophthalmic gel formulation comprising about 0.1% to about 10% povidone-iodine (PVP-I); about 30% to about 99% dimethyl sulfoxide (DMSO); and about 1% to about 10% gelling agent; wherein, each ingredient in the composition is ophthalmically acceptable, and the ophthalmic gel composition exhibits greater efficacy in treating infectious conditions of the eye or eyelid, compared to a liquid composition substantially free of a gelling agent and comprising about 0.1% to about 10% povidone-iodine and about 30% to about 99% DMSO.
  • PVP-I povidone-iodine
  • DMSO dimethyl sulfoxide
  • a preferred ophthalmic gel composition comprises about 0.5% to about 5% PVP-I.
  • a more preferred ophthalmic gel composition comprises about 1% to about 3% PVP-I, and a most preferred ophthalmic gel composition comprises about 1% PVP-I.
  • a composition of the invention preferably comprises povidone-iodine, or PVP-I having an average molecular weight greater than 10,000. More preferably, the composition of the invention comprises PVP-I having an average molecular weight between about 20,000 to about 1,000,000.
  • One preferred embodiment comprises high molecular weight (HMW) PVP-I.
  • a preferred ophthalmic gel composition comprises about 30%/o to about 70% DMSO.
  • a more preferred ophthalmic gel composition can comprise about 40% to about 49% DMSO, and even more preferably, about 44% DMSO.
  • a preferred ophthalmic gel composition comprises about 2% to about 5% gelling agent.
  • a more preferred ophthalmic gel composition can comprise about 4% gelling agent.
  • a particularly useful composition which has been prepared for use in treating infection of the eye or eyelid comprises 1% PVP-I; 44% DMSO; 4% hydroxyethylcellulose; and 51% aqueous solvent.
  • a preferred aqueous solvent is water or isotonic buffer.
  • An ophthalmic gel composition of the invention can include a gelling agent, as is well known in the art, selected from a gum, agar, carrageenan, petrolatum, or a cellulosic polymer or the like.
  • a gelling agent selected from a gum, agar, carrageenan, petrolatum, or a cellulosic polymer or the like.
  • One preferred cellulosic polymer useful as a gelling agent is hydroxyethyl cellulose (HEC).
  • An alternative cellulosic polymer gelling agent is hydroxymethyl cellulose.
  • the subject invention further concerns a method for treating, or inhibiting the growth of, warts, including genital warts, caused by human papilloma virus (HPV) or molluscum contagiosum virus (MCV).
  • the method comprises, generally, one or more as needed administrations or topical applications of a topical gel of the invention, namely, a topical composition comprising an iodophor, DMSO, and a gelling agent, to the site, until the wart is eliminated, or its growth is substantially inhibited.
  • the subject gel composition is administered directly onto the wart as needed (PRN), preferably at least once per day (QD), or more preferably at least two times per day (BID) until results are seen, typically for about one week, up to about 24 weeks.
  • PRN wart as needed
  • QD at least once per day
  • BID at least two times per day
  • a method of the subject invention comprises treating an infection of the skin, including skin of genitalia, by providing a composition as described herein, and applying an effective amount of a topical gel composition to a site of the infection as needed to reduce or eliminate the infection caused by or associated with one or more infectious agents selected from the group consisting of bacteria, demodex, fungus or yeast, and virus.
  • a preferred method of treating viral infection of the skin or genitalia comprises administration or application to a skin infection caused by or associated with human papilloma virus (HPV) or molluscum contagiosum virus (MCV).
  • HPV human papilloma virus
  • MCV molluscum contagiosum virus
  • the subject method can be used to reduce or eliminate a viral wart.
  • the method can be carried out by application or administration of the composition to a skin infection on the skin of the face or genitalia.
  • Yet another aspect of the invention comprises a method of treating an infectious condition of the eye or eyelid, comprising applying an effective amount of a stable, topical ophthalmic gel composition to a site of the infection to reduce or eliminate the infection.
  • the method of the invention can be useful in treating blepharitis, conjunctivitis, corneal ulcer, HSV keratitis, conjunctival neoplasia, AC inflammation, post-operative endophthalmitis, and endophthalmitis after intravitreal or intracameral injection, which is caused by or associated with one or more infectious agents such as bacteria, demodex, fungus or yeast, or virus.
  • the present invention concerns a topical gel composition
  • a topical gel composition comprising an antiseptic agent, a penetration enhancer, and a gelling agent.
  • the composition comprises povidone-iodine as the antiseptic agent, dimethylsulfoxide (DMSO) as the penetration enhancer, and a cellulosic gelling agent, such as hydroxyethylcelluose (HEC).
  • DMSO dimethylsulfoxide
  • HEC hydroxyethylcelluose
  • the composition can, optionally, further comprise a lubricant or co-solvent, or other acceptable excipients.
  • a composition for treating an ophthalmic condition, such as blepharitis can include an ophthalmically acceptable excipient.
  • the subject composition is surprisingly useful for the treatment of viral wart infection of the skin, as well as viral, demodex, fungal/yeast or bacterial infection of the eyelids, conjunctiva, cornea, ocular surface and Meibomian glands, which can cause blepharitis.
  • a specific but non-limiting example of a formulation of the invention providing a useful pharmaceutical preparation comprises solid PVP-I dissolved or suspended in DMSO with one or additional co-solvents in solution and prepared as a gel or semi-solid.
  • DMSO can be added to aqueous solutions of PVP-I.
  • DMSO can be present as a co-solvent with water in the range of 10%-99%.
  • excipients such as sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous and water, as well as others known to those skilled in the art.
  • Percentages set forth herein are (w/w), with respect to the specified component in the overall composition, unless otherwise indicated.
  • a composition comprising 1% PVP-I and 45% DMSO has 1% PVP-I by weight, with respect to the total composition.
  • a composition comprises povidone-iodine in the range of about 0.01% to about 15%.
  • a composition comprises povidone-iodine in the range between 0.05% and 12.5%.
  • a composition comprises povidone-iodine in the range between 0.05% and 10.0%.
  • a composition comprises povidone-iodine in the range between 0.1% and 10.0%.
  • a composition comprises povidone-iodine in the range between 0.1% and 5.0%. In another embodiment, a composition comprises povidone-iodine in the range between 0.25% and 9.0%. In another embodiment, a composition comprises povidone-iodine in the range between 0.2% and 2.5%. In another embodiment, a composition comprises povidone-iodine in the range between 0.5% and 7.5%. %. In another embodiment, a composition comprises povidone-iodine in the range between 0.5% and 1.0%. In another embodiment, a composition comprises povidone-iodine in the range between 0.75% and 5.0%, and in yet another embodiment, between 1.0% and 4.0%. In an embodiment, a composition comprises povidone-iodine in the range of about 0.1% to about 2.5%, about 0.2% to about 2.0%, about 0.3% to about 1.0%, and about 0.4% to about 0.75%.
  • a composition comprises povidone-iodine of about 0.01%, about 0.05%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.4/0%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, about 1.00%, about 1.05%, about 1.10%, about 1.15%, about 1.20%, about 1.25%, about 1.30%, about 1.35%, about 1.40%, about 1.45%, about 1.50%, about 1.55%, about 1.60%, about 1.65%, about 1.70%, about 1.75%, about 1.80%, about 1.85%, about 1.90%, about 1.95%, about 2.00%, about 2.05%, about 2.10%, about 2.15%, about 2.20%, about 2.25%, about 2.30%, about 2.35%, about 2.40%, about 2.45%, about 2.00%
  • a composition comprises PVP-I in the range of about 0.01% to about 15%. In another embodiment, a composition comprises PVP-1 in the range between 0.05% and 12.5%. In another embodiment, a composition comprises PVP-I in the range between 0.05% and 10.0%. In another embodiment, a composition comprises PVP-I in the range between 0.1% and 10.0%. In another embodiment, a composition comprises PVP-I in the range between 0.1% and 5.0%. In another embodiment, a composition comprises PVP-I in the range between 0.25% and 9.0%. In another embodiment, a composition comprises PVP-I in the range between 0.2% and 2.5%. In another embodiment, a composition comprises PVP-I in the range between 0.5% and 7.5%. %.
  • a composition comprises PVP-I in the range between 0.5% and 1.0%. In another embodiment, a composition comprises PVP-I in the range between 0.75% and 5.0%, and in yet another embodiment, between 1.0% and 4.0%. In an embodiment, a composition comprises PVP-I in the range of about 0.1% to about 2.5%, about 0.2% to about 2.0%, about 0.3% to about 1.0%, and about 0.4% to about 0.75%.
  • a composition comprises PVP-I at about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.25%, about 1.50%, about 1.75%, about 2.0%, about 2.25, about 2.5%, about 3.0%, about 3.5%, about 4%, about 4.5%, about 5%, about 7.5%, about 10%, about 12.5, or about 15.0%.
  • a composition comprises PVP-I at about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.05%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, about 1.00%, about 1.05%, about 1.10%, about 1.15%, about 1.20%, about 1.25%, about 1.30%, about 1.35%, about 1.40%, about 1.45%, about 1.50%, about 1.55%, about 1.60%, about 1.65%, about 1.70%, about 1.75%, about 1.80%, about 1.85%, about 1.90%, about 1.95%, about 2.006, about 2.05%
  • a composition comprises PVP-I at about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%.
  • a composition comprises PVP-I at about 0.1% or less, about 0.5% or less, about 1% or less, about 2% or less, about 3% or less, about 4% or less, about 5% or less, about 6% or less, about 7% or less, about 8% or less, about 9% or less or about 10% or less.
  • a composition comprises PVP-I at about 0.01% or more, about 0.05% or more, about 0.075% or more, about 0.1% or more, about 0.2% or more, about 0.3% or more, about 0.4% or more, about 0.5% or more, about 0.6% or more, about 0.7% or more, about 0.8% or more, about 0.9% or more, about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more or about 10% or more.
  • a composition comprises PVP-I at 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.00%, 3.50%, 4.0%, 4.5%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0% or 10.0%.
  • a composition comprises DMSO and PVP-I. In an embodiment, a composition consists essentially of DMSO and PVP-I. In an embodiment, a composition consists of DMSO and PVP-I. In an embodiment, a composition is anhydrous. In an embodiment, a composition is substantially anhydrous. In an embodiment, a composition comprises a measurable amount of water.
  • anhydrous DMSO is used in a composition.
  • substantially anhydrous DMSO is used in a composition. It will be understood by one of skill in the art that DMSO can be produced and/or obtained in differing grades, and that one of the variables among DMSO preparations of different grades is the water content.
  • DMSO may be completely anhydrous (also referred to herein simply as “anhydrous”), substantially anhydrous, or may contain water to a measurable degree. It will be understood that the amount of measurable water in a DMSO preparation may vary based on limitations of the instrumentation and techniques used to make such measurements.
  • DMSO that is not completely anhydrous may be substantially anhydrous and contain water at a level below levels of detectability.
  • DMSO that is not completely anhydrous may contain water, wherein the water content is about at least 0.01%, about at least 0.02%, about at least 0.03%, about at least 0.04%, about at least 0.05%, about at least 0.06%, about at least 0.07%, about at least 0.08%, about at least 0.09%, about at least 0.1%, about at least 0.2%, about at least 0.3%, about at least 0.4%, about at least 0.5%, about at least 0.6%, about at least 0.7%, about at least 0.8%, about at least 0.9%, about at least 1.0%, about at least 1.5%, about at least 2.0%, about at least 2.5%, about at least 5%, about at least 7.5%, about at least 10%, about at least 12.5%, or greater.
  • DMSO that is not completely anhydrous may contain water, wherein the water content is about less than 0.01%, about less than 0.02%, about less than 0.03%, about less than 0.04%, about less than 0.05%, about less than 0.06%, about less than 0.07%, about less than 0.08%, about less than 0.09%, about less than 0.1%, about less than 0.2%, about less than 0.3%, about less than 0.4%, about less than 0.5%, about less than 0.6%, about less than 0.7%, about less than 0.8%, about less than 0.9%, about less than 1.0%, about less than 1.5%, about less than 2.0%, about less than 2.5%, about less than 5%, about less than 7.5%, about less than 10%, about less than 12.5%, or greater. It will be understood that DMSO may contain one or more other impurities in addition to water.
  • a composition comprises at least one of United States Pharmacopeial Convention (USP) grade DMSO, Active Pharmaceutical Ingredient (API) grade DMSO, analytical grade DMSO, and American Chemical Society (ACS) Spectrophotometric grade DMSO.
  • USP United States Pharmacopeial Convention
  • API Active Pharmaceutical Ingredient
  • ACS American Chemical Society
  • a composition comprises DMSO having ⁇ 0.1% water by KF titration and >99.9% determined on an anhydrous basis.
  • the percent amount of DMSO in a composition is described in a weight-to-weight (w/w) ratio with respect to one or more other components of the composition, unless otherwise indicated.
  • the weight percent DMSO is the balance of the weight percent after addition of PVP-I.
  • a composition may comprise 1 weight percent (1%) PVP-I and 99 weight percent (99%) DMSO.
  • the DMSO component of the composition may be completely anhydrous, substantially anhydrous, or may contain water to a measurable degree.
  • the weight percent DMSO is the balance of the weight percent after addition of PVP-I and any other components (e.g., co-solvent, water, additional active ingredient, etc.). In an embodiment, the weight percent DMSO is the balance of the weight percent after addition of iodophor and other components, if any. In an embodiment, the weight percent penetrant in a composition is the balance of the weight percent after addition of iodophor and other components, if any.
  • a composition comprises DMSO in the range of 50% to 99.99%. In an embodiment, a composition comprises DMSO in the range of 1% to 99.99%. In another embodiment, a composition comprises DMSO in the range of 5% and 99.9%. In another embodiment, a composition comprises DMSO in the range of 10% and 99.9%. In another embodiment, a composition comprises DMSO in the range of 20% and 99.9%. In another embodiment, a composition comprises DMSO in the range of 30% and 99.9%. In another embodiment, a composition comprises DMSO in the range of 40% and 99.9%. In another embodiment, a composition comprises DMSO in the range of 50% and 99.9%. In another embodiment, a composition comprises DMSO in the range of 60% and 99.9%. In another embodiment, a composition comprises DMSO in the range of 70% and 99.9%. In another embodiment, a composition comprises DMSO in the range of 80% and 99.9%, and in yet another embodiment, between 90% and 99.9%.
  • a composition comprises DMSO in weight percent of about at least 50%, about at least 55%, about at least 60%, about at least 65%, about at least 70%, about at least 75%, about at least 80%, about at least 85%, about at least 87.5%, about at least 90%, about at least 91%, about at least 92%, about at least 93%, about at least 94%, about at least 95%, about at least 96%, about at least 97%, about at least 98%, about at least 99%, or about at least 99.9%.
  • a composition comprises DMSO at about 1%.
  • a composition comprises DMSO at about 1%, about 1.5%, about 2%, about 2.5, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9.0, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, about 15.5%, about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about 18.5%, about 19%, about 19.5%, about 20%, about 20.5%, about 21%, about 21.5%, about 22%, about 22.5%, about 23%, about 23.5%, about 24%, about 24.5%, about 25%, about 25.5%, about 26%, about 26.5%, about 27%, about 27.5%, about 28%, about 28.5%, about 290%, about 29.5%, about 30%, about 30
  • a composition comprises DMSO in weight percent of about 40% to about 50%, about 41% to about 50%, about 42% to about 50%, about 43% to about 50%, about 44, to about 50%, about 45% to about 50%, about 46% to about 50%, about 47% to about 50%, about 48% to about 50%, about 49% to about 50%, 40% to about 49%, about 41% to about 49%, about 42% to about 49%, about 43% to about 49%, about 44% to about 49%, about 45% to about 49, about 46% to about 49%, about 47% to about 49%, about 48% to about 49%, about 40% to about 48%, about 41%6 to about 48%, about 42% to about 48%, about 43% to about 48%, about 44% to about 48%, about 45% to about 48%, about 46% to about 48%, about 47% to about 48%, 40% to about 47%, about 41% to about 47%, about 42% to about 47%, about 43% to about 47%, about 44% to about 47%, about 48%
  • a composition comprises DMSO in weight percent of about 10% to about 30% or about 10% to about 49%. In one embodiment, a composition comprises up to 65% DMSO in weight percent. In one embodiment, a composition comprises up to 60% DMSO in weight percent. In one embodiment, a composition comprises up to 55% DMSO in weight percent. In one embodiment, a composition comprises up to 50% DMSO in weight percent. In one embodiment, a composition comprises up to 49% DMSO in weight percent. In one embodiment, a composition comprises up to 45% DMSO in weight percent. In one embodiment, a composition comprises up to 44% DMSO in weight percent.
  • a composition comprises a co-solvent in the range of 1% to 99.99%. In another embodiment, a composition comprises a co-solvent in the range of 5% and 99.9%. In another embodiment, a composition comprises a co-solvent in the range of 10% and 99.9%. In another embodiment, a composition comprises a co-solvent in the range of 20% and 99.9%. In another embodiment, a composition comprises a co-solvent in the range of 30% and 99.9%. In another embodiment, a composition comprises a co-solvent in the range of 40% and 99.9%. In another embodiment, a composition comprises a co-solvent in the range of 50% and 99.9%.
  • a composition comprises a co-solvent in the range of 60% and 99.9%. In another embodiment, a composition comprises a co-solvent in the range of 70% and 99.9%. In another embodiment, a composition comprises a co-solvent in the range of 80% and 99.9%, and in yet another embodiment, between 90% and 99.9%.
  • a composition comprises a co-solvent at about 1%. In other embodiments, a composition comprises a co-solvent at about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%
  • co-solvents examples include, but are not limited to, alcohols, silicones, polyethylene glycol, propylene glycol, glycerin, petrolatum, hydroxymethylcellulose, methylcellulose, and combinations thereof.
  • a co-solvent is propylene glycol.
  • a composition comprises DMSO in the range of about 0.01% to 99.99% and further comprises at least one penetrant in the range of 0.01% to about 99.99%.
  • a composition comprises DMSO and further comprises at least one penetrant in the range of about 0.1% to about 50%.
  • a composition comprises DMSO and further comprises at least one penetrant in the range between about 5% and about 50%.
  • a composition comprises DMSO and further comprises at least one penetrant in the range between about 10% and about 99%.
  • a composition comprises DMSO, at least one co-solvent, and at least one penetrant.
  • a co-solvent is also a penetrant.
  • compositions may include pharmaceutically acceptable salts of compounds in the composition.
  • compositions comprise acid addition salts of the present compounds.
  • compositions comprise base addition salts of the present compounds.
  • pharmaceutically acceptable salts or complexes refers to salts or complexes (e.g., solvates, polymorphs) that retain the desired biological activity of the parent compound and exhibit minimal, if any, undesired toxicological effects.
  • compositions encompassed herein comprise pharmaceutically acceptable excipients such as those listed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995; Ghosh, T. K; et al. TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997), hereby incorporated herein by reference, including, but not limited to, protectives, adsorbents, demulcents, emollients, preservatives, antioxidants, moisturizers, buffering agents, solubilizing agents, skin-penetration agents, and surfactants.
  • pharmaceutically acceptable excipients such as those listed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995; Ghosh, T. K; et al. TRANSDERMAL AND TOPICAL
  • Protectives and adsorbents include, but are not limited to, dusting powders, zinc sterate, collodion, dimethicone, silicones, zinc carbonate, aloe vera gel and other aloe products, vitamin E oil, allantoin, glycerin, petrolatum, and zinc oxide.
  • Demulcents include, but are not limited to, benzoin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl alcohol.
  • Emollients include, but are not limited to, animal and vegetable fats and oils, myristyl alcohol, alum, and aluminum acetate.
  • Preservatives include, but are not limited to, chlorine dioxide, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercurial agents, such as phenylmercuric nitrate, phenylmercuric acetate, and thimerosal; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, and benzyl alcohol; antibacterial esters, for example, esters of parahydroxybenzoic acid; and other anti-microbial agents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin.
  • quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride
  • mercurial agents such as phenylmercuric nitrate, pheny
  • Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid.
  • Suitable moisturizers include, but are not limited to, glycerin, sorbitol, polyethylene glycols, urea, and propylene glycol.
  • Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.
  • Suitable skin-penetration agents include, but are not limited to, ethyl alcohol, isopropyl alcohol, octylphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol. N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate); and N-methylpyrrolidone.
  • a composition comprises PVP-I, DMSO, and propylene glycol. In an embodiment, a composition comprises 2% PVP-I, 65% DMSO, 23% and 10% propylene glycol. In an embodiment, the composition is substantially anhydrous.
  • a composition comprises PVP-I, DMSO, hydroxymethylcellulose, propylene glycol and glycerin. In an embodiment, a composition comprises 2% PVP-I, about 40% DMSO, and 10-33% propylene glycol and at least one additional inactive ingredient.
  • the composition includes 1-3%/o PVP-I, 40-49% DMSO, 8-15% alcohol, 18-25% propylene glycol, 0-2% gelling agents, and 0-3% water.
  • the composition includes aprotic solvents.
  • the composition includes 1-3% PVP-I, 10-30% DMSO, 10-35% propylene glycol, 0-2% gelling agents, and 0-3% water.
  • the composition includes aprotic solvents.
  • the invention comprises DMSO 40-50% (w/w), 0.5%-5% PVP-I (w/w) and hydroxypropyl methylcellulose or hydroxymethyl cellulose or hydroxyethyl cellulose.
  • the composition is a solution; semi-solid, e.g., a gel, suspension, ointment or cream; tincture; foam; aerosol or another common pharmaceutical dosage form.
  • the composition is a 2% PVP-I/44% DMSO solution.
  • the composition is a 1% PVP-I/45% DMSO solution.
  • the composition is a 1.5% PVP-I/46% DMSO solution.
  • the composition is a 2.5% PVP-I/43% DMSO solution.
  • the composition is a 1% PVP-I/99% DMSO solution.
  • the composition is a 2% PVP-I/65% DMSO solution.
  • the composition is a 2% PVP-I/65% DMSO/10-25% propylene glycol solution.
  • the formulations are stable at room temperature 25° C. for at least 6 months, 12 months, 18 months and 24 months. Stability is defined as where the final PVP-I concentration is at least 85%-120%, according to the USP method, of the labeled concentration.
  • the formulations are stable at room temperature 2-8° C. for at least 6 months, 12 months, 18 months and 24 months. Stability is defined as where the final PVP-I concentration is at least 85%-120%, according to the USP method of the labeled concentration (e.g. if the label is 2% PVP-I providing for 0.2% iodine, therefore 90% would be 0.18 elemental iodine).
  • the formulations are stable at room temperature ⁇ 10 to ⁇ 25° C. for at least 6 months, 12 months, 18 months and 24 months. Stability is defined as where the final PVP-I concentration is at least 85%-120%, according to the USP method of the labeled concentration (e.g. if the label is 2% PVP-I providing for 0.2% iodine, therefore 90% would be 0.18 elemental iodine).
  • the formulations are stable at room temperature 15-30° C. for at least 6 months, 12 months, 18 months and 24 months. Stability is defined as where the final PVP-I concentration is at least 85%-120%, according to the USP method, of the labeled concentration (e.g. if the label is 2% PVP-I providing for 0.2% iodine, therefore 90% would be 0.18 elemental iodine).
  • the formulations are stable at room temperature 40° C. for at least 1 months, 3 months, 6 months, 12 months, 18 months and 24 months. Stability is defined as where the final PVP-I concentration is at least 85%-120%, according to the USP method of the labeled concentration (e.g. if the label is 2% PVP-I providing for 0.2% iodine, therefore 90% would be 0.18 elemental iodine).
  • PVP-I aqueous solutions are difficult to stabilize at low PVP-I concentrations over a long period of time.
  • concentrations of PVP-I less than about 0.7% (w/w, aqueous) PVP-I aqueous solutions rapidly decay to yield complex mixtures of iodinated and iodine-free constituents.
  • PVP-I solutions as low as 0.1% can be easily prepared and maintained as stable compositions in Type I glass or HDPE plastic for long periods of time. Also as described herein, hydrated DMSO solutions prepared from aqueous PVP-I demonstrate increased stability for the PVP-I component.
  • a composition comprises dry, solid or powdered PVP-I dissolved or suspended in a composition comprising or consisting of DMSO.
  • DMSO is added to an aqueous preparation comprising or consisting of PVP-I.
  • a therapeutically-effective pharmaceutical composition is prepared using solid PVP-I, which is dissolved or suspended in DMSO.
  • the composition is anhydrous.
  • the composition is substantially anhydrous.
  • DMSO can be added to aqueous solutions of PVP-I to prepare a therapeutically-effective pharmaceutical composition.
  • DMSO is used in the range of 500%-99% as a co-solvent with water and other non-aqueous co-colvents.
  • a formulation includes one or more excipients.
  • excipients include, but are not limited to, sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous and water, as well as others known to those skilled in the art.
  • a composition is prepared by adding 10% PVP-I (w/v, aqueous) to pure DMSO q.s. to yield a resulting solution of 1% PVP-I (w/w) with DMSO.
  • compositions are prepared by dissolving solid PVP-I in pure DMSO q.s to obtain any of 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1.0%, 1.25%, 1.5%, 2.0%, or 2.5% PVP-I (w/w), as well as about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1.0%, about 1.25%, about 1.5%, about 2.0%, or about 2.5% PVP-I (w/w) compositions, with DMSO as the solvent.
  • compositions are prepared by dissolving solid PVP-I in pure DMSO q.s to obtain any composition set forth, described, and/or encompassed herein.
  • Similar compositions comprising aqueous PVP-I (with and without excipients commonly used and/or known in the art) and DMSO can be prepared from a stock 10% PVP-I aqueous solution and pure DMSO.
  • any starting composition of PVP-I, solid or liquid may be used when the appropriate dilutions and adjustments are made to result in the desired final PVP-I concentration.
  • any starting composition of iodophor or elemental iodine may be used when the appropriate dilutions and adjustments are made to result in the desired final iodophor or elemental iodine concentration, respectively.
  • a therapeutic composition is prepared by optimizing one or more compounds for use in a dosage form different than that which is typically used for the compound.
  • a compound that is not typically administered in a topical dosage form is developed for use in a topical dosage form.
  • the chemical and biological assays required for such development are known to one of skill in the art. The disclosure herein provides the skilled artisan with the guidance as to how to prepare such compounds and compositions comprising such compounds.
  • a method of treating a subject having an ocular surface disease complicated by microbial colonization and/or infection includes administration of a composition set forth, described, and/or encompassed herein to treat the ocular surface disease, and the treatment of the ocular surface disease includes at least one of preventing or slowing the progression of the infection, preventing the spread of the infection, eradicating at least some of the infection, and eradicating the entire infection.
  • a therapeutic composition is administered on a schedule once a day. In an embodiment, a therapeutic composition is administered twice a day. In an embodiment, a therapeutic composition is administered three times a day, four times a day, five times a day, or more. In an embodiment, a therapeutic composition is administered less frequently than once a day. In an embodiment, a therapeutic composition is administered once every two days, once every three days, once every four days, once every five days, once every six days, or once every seven days. In an embodiment, a therapeutic composition is administered less frequently than once a week. In an embodiment, a therapeutic composition is administered once a month. In an embodiment, a therapeutic composition is administered twice a month.
  • a therapeutic dosing regimen is continued for at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, or at least seven days. In an embodiment, a therapeutic dosing regimen is continued for at least one week, at least two weeks, at least three weeks, at least four weeks, at least six weeks, at least eight weeks, at least ten weeks, at least twelve weeks, at least fourteen weeks, or at least sixteen weeks. In an embodiment, a therapeutic dosing regimen is continued for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least nine months, or at least twelve months.
  • compositions described in this invention include the formulation of creams, petrolatum balms, salves, sprays, and other formulations well known to those in the art suitable for topical administration to the ocular surface or are “ophthalmically acceptable” compositions.
  • Subjects are dosed twice per day for a period of 12 weeks. Subjects are male or female, between the ages of 10-99, presenting with visible verrucous warts.
  • Liquid formulations are generally be expected to be more efficacious than gel formulations because the lower viscosity, compared to that of gels, is expected to allow the active ingredient to be more easily transferred across the epidermal layer or the generally less penetrable, horny outer layer of the wart.
  • Dosing of the gel formulation comprises administration of an approximately 1 ⁇ 2 inch ribbon directly to the wart (2 ⁇ /day for 12 weeks) and/or the area immediately surrounding the wart.
  • Dosing of the liquid formulation comprises administration of 1-5 drops, typically 2-3 drops, of the composition directly to the wart and/or area immediately surrounding the wart.
  • the PVP-I 2% gel formulation has been found to be more efficacious than the PVP-I 2% solution.
  • the solution takes 1-2 minutes to fully absorb, and as molluscum primarily occurs in the pediatric population this waiting period is often not adhered to and some of the solution is inadvertently wiped off.
  • the gel has much better contact time and does not require a waiting period once applied to the skin.
  • a complete clearance was seen in 5/11 (45%) patients and partial clearance in 6/11 (55%) patients, with 79/98 (81%) total lesions resolving.
  • For the gel a complete response was seen in 20/28 (71%) patients and partial response seen in 8/28 (29%) patients, with 268/288 (93%) of total lesions clearing.
  • a liquid formulation was expected to provide adequate efficacy against warts and blepharitis. Most wart treatments are liquids. Surprisingly, it was found that a gel formulation provides unexpected advantages and increased efficacy compared with similar concentrations of PVP-I in a liquid formulation.
  • This patient was suffering from anterior blepharitis.
  • the anterior lid margin demonstrates madarosis, collarettes, scurf, lash debris and bacterial overgrowth.
  • the lid margin may also be erythematous along with the conjunctiva and a decreased tear break up time is present.
  • the condition had persisted for over 7 years and taken a chronic course.
  • the patient had tried numerous antibiotics, steroids, lid scrubs, omega 3 fatty acids, and anti-inflammatories without benefit.
  • Prepared was a composition as disclosed herein using 1.0% PVP-I in 30% DMSO with polypropylene glycol and hydroxymethylcellulose. The patient was treated by applying the solution topically to the eyelid and conjunctiva twice daily.
  • This patient was suffering from posterior blepharitis.
  • the posterior lid margin demonstrates meibomian gland thickening, keratinization, fat saponification, and dilated, telangectatic lid vessels.
  • the lid margin may also be erythematous along with the conjunctiva and decreased tear break up time is evident.
  • the condition had persisted for over 7 years and taken a chronic course.
  • the patient had tried numerous antibiotics, steroids, lid scrubs, omega 3 fatty acids and anti-inflammatories without benefit.
  • Prepared was a composition as disclosed herein using 0.2% PVP-I in 35%% DMSO with hydroxyethyl cellulose.
  • the patient was treated by applying the solution topically to the eyelid and conjunctiva twice daily. Within one week improvement was noted in and around the eyelid. After two weeks the condition rapidly improved, as the conjunctival erythema abated, tear break up time and dry eye symptoms normalized. Close inspection of the posterior lid eyelid margin revealed healthy meibomian seceretions, attenuation of posterior lid blood vessels and lack of erythema.
  • This patient was suffering from Rosacea blepharitis.
  • the posterior lid margin demonstrates meibomian gland thickening, keratinization, fat saponification, and dilated, telangectatic lid vessels.
  • Anterior lid margin may also demonstrate scurf and bacterial overgrowth.
  • the lid margin may also be erythematous along with the conjunctiva and a decreased tear break up time is present.
  • the condition had persisted for over 7 years and taken a chronic course.
  • the patient had tried numerous antibiotics, steroids, lid scrubs, omega 3 fatty acids and anti-inflammatories without benefit.
  • Slit lamp biomicroscopic examination revealed bilateral anterior lid margin erythema, crusting and thickening. Lash examination revealed some breakage with scurf-like deposition. Inspection of the posterior eyelids revealed inspissated meibomian glands with capping and turbid secretions. Further towards the posterior tarsal area, dilated, engorged telangiectatic vessels were present. The marginal lid erythema extended not only to the tarsal plate, but also to the inferior bulbar conjunctiva. Tear break-up time was notably decreased and corneae revealed inferior, bilateral punctate epithelial erosions. A diagnosis of rosacea blepharoconjunctivitis was made.
  • the patient was given a topical gel of 1% PVP-I in a dimethylsulfoxide (DMSO) vehicle that was prepared from a licensed compounding pharmacy.
  • DMSO dimethylsulfoxide
  • the treatment was administered twice daily and delivered by rubbing the gel onto the lash line and eyelid.
  • the patient was instructed to decrease the gel to once daily, but continue treatment for a total of one month.
  • the posterior lid margin vessels and telangiectasia had begun to attenuate and involute.
  • meibomian capping was no longer present and secretions were less viscous. Besides occasional mild tingling at the application site, the patient reported no other adverse effects
  • This patient was suffering from anterior Demodex blepharitis.
  • the anterior lid margin demonstrates madarosis, collarettes in cylindrical pattern and lash debris. Decreased tear break up time is also evident.
  • the posterior lid margin may also be erythematous and demonstrate meibomian inspissation, fat saponification, and bacterial overgrowth.
  • the patient had persisted for over 7 years and taken a chronic course.
  • the patient had tried numerous antibiotics, steroids, tea tree oils, lid scrubs omega 3 fatty acids and anti-inflammatories without benefit.
  • Cilia were epilated and examined under the microscope positively identifying Demodex folliculorum.
  • This patient was suffering from blepharoconjunctivits.
  • the anterior lid margin demonstrates madarosis, collarettes, scurf, lash debris and bacterial overgrowth.
  • the posterior lid margin may also be erythematous, and demonstrate meibomian inspissation, capping, and keratinization.
  • a hallmark of this process is abundant conjunctival injection which is secondary to anterior and posterior lid inflammation.
  • the condition had persisted for over 1 week with an acute course.
  • the patient had tried numerous antibiotics, steroids, lid scrubs, omega 3 fatty acids, and anti-inflammatories without benefit.
  • Prepared was a composition as disclosed herein using 0.3% PVP-I in 33% DMSO with glycerin.
  • the patient was treated by applying the solution topically to the eyelid and conjunctiva twice daily. Within one week improvement was noted in and around the eyelid. After two weeks the condition rapidly improved, as tear break up time and dry eye symptoms normalized. Close inspection of the anterior lid eyelid margin revealed healthy cilia without associated debris or bacterial overgrowth. Posterior lid margin inspection revealed healthy meibomian secretions and decreased lid erythema. The conjunctival examination revealed quiet and healthy tissue without inflammation.
  • This patient was suffering from adenoviral conjunctivitis.
  • This common type of conjunctivitis follows a recent viral upper respiratory infection or contact with another infected person. Pre-auricular adenopathy is often present.
  • the conjunctiva demonstrated diffuse injection with chemosis. There was frequent clear ocular discharge present. Eyelid eversion revealed 3+ follicular reaction with few scattered petechiae.
  • RPS Adenodetector sampling identified the causative agent to be an Adenovirus serotype. The patient had tried numerous antibiotics, steroids, lid scrubs and anti-inflammatories without benefit.
  • Epidemic Adenoviral Conjunctivitis Treated with 0.5% PVP-I in 41.5%% USP Grade DMSO with Hydroxyethyl Cellulose
  • This patient was suffering from epidemic adenoviral conjunctivitis.
  • This type of conjunctivitis follows a recent viral upper respiratory infection or contact with another infected person. Pre-auricular adenopathy is often present.
  • the conjunctiva demonstrated diffuse injection with chemosis along with pseudomembrane formation. There was frequent clear ocular discharge present. Eyelid eversion revealed 3+ follicular reaction with few scattered petechiae. Corneal examination showed multifocal, sub-epithelial infiltrates.
  • RPS Adenodetector sampling identified the causative agent to be an Adenovirus serotype. The patient had tried numerous antibiotics, steroids, lid scrubs and anti-inflammatories without benefit.
  • the patient was treated by applying the solution topically to the eyelid and conjunctiva three times daily. Within three days improvement was noted in and around the eyelid. At one week the condition was resolved, as the conjunctival erythema, discharge, follicles and inflammatory membranes were no longer present.
  • Herpes Simplex Virus Epithelial Keratitis Treated with 2.0% PVP-I in 49% USP Grade DMSO with Glycerin
  • herpes simplex virus epithelial keratitis This patient was suffering from herpes simplex virus epithelial keratitis. In this type of keratitis there is often active replicating virus present within epithelial dendrites. With immune system weakening, the virus reactivates in the sensory ganglia and descends to infect the cornea. It can often manifest as recurrent disease. In this patient, the conjunctiva demonstrated diffuse injection and the cornea showed staining epithelial ulcerations in serpentine or dentritic form with terminal bulbs. Millipore testing reveals herpes simplex virus as the causative agent. The patient had tried numerous antibiotics, steroids, oral and topical anti-virals and anti-inflammatories without benefit.
  • Herpes Simplex Virus Stromal Keratitis Treated with 0.15% PVP-I in 44% USP Grade DMSO with Hydroxyethyl Cellulose
  • This patient was suffering from herpes simplex virus stromal keratitis. In this type of keratitis there is often immune activation of the host secondary to molecular mimicry causing stromal corneal swelling. There may or may not be active replicating virus. It can often manifest as recurrent disease. In this patient, the conjunctiva demonstrated diffuse injection and the cornea showed diffuse corneal swelling with opacification. The patient had tried numerous antibiotics, steroids, oral and topical anti-virals and anti-inflammatories without benefit. Prepared was a composition as disclosed herein using 0.15% PVP-I in 44% DMSO with hydroxyethyl cellulose. The patient was treated by applying the solution topically to the eye three times daily.
  • the stromal edema began to clear and the patient was without any staining dendrites. At one week the condition was resolved and there was no evidence of the previous corneal lesions, cicatrization, or neovascularization. The conjunctiva was white and quiet.
  • Herpes Simplex Virus Endothelial Keratitis Treated with 1.4% PVP-I in 38% USP Grade DMSO with Hydroxyethyl Cellulose
  • This patient was suffering from herpes simplex virus endothelial keratitis.
  • this type of keratitis there is often immune activation of the host secondary to molecular mimicry directed at endothelial cells.
  • the conjunctiva demonstrated diffuse injection and the cornea showed disciform endothelial inflammation with keratic precipitates.
  • Some stromal corneal edema was also present.
  • the anterior chamber revealed rare inflammatory cells and mild trabeculitis. The patient had tried numerous antibiotics, steroids, oral and topical anti-virals and anti-inflammatories without benefit.
  • Herpes Zoster Ophthalmicus Treated with 1.8% PVP-I in 40% USP Grade DMSO with Petralatum
  • This patient was suffering from herpes zoster virus epithelial keratitis.
  • herpes zoster virus epithelial keratitis In this type of keratitis there is often viral infection within the eye along with erythematous macules and excoriations in dermatomal distribution. With immune system weakening, the herpes zoster virus is reactivated within the ophthalmic division of the trigeminal nerve.
  • the conjunctiva demonstrated diffuse injection and the cornea showed rose bengal staining epithelial “stuck on” dendrites in without terminal bulbs.
  • the underlying corneal stroma demonstrated central edema without keratic precipitates. Fundus examination was negative for vasculitis.
  • Prepared was a composition as disclosed herein using 1.8% PVP-I in 40% DMSO with petralatum.
  • This patient was suffering from a bacterial corneal ulceration. In this type of infection there is often a history of contact lens use, however, this is not a prerequisite. Bacteria is introduced into the eye through a small break in the epithelium and gains foothold to the underlying structures. In this patient, the conjunctiva demonstrated diffuse injection with pyogenic discharge. The cornea demonstrated a central, three millimeter circular infiltrate with overlying central epithelial defect. The infiltrate induced stromalysis and the resultant cornea had thinned by approximately thirty percent. There was a one millimeter layered hypopyon in the anterior chamber. Corneal cultures were taken, and Coagulase negative Streptococcal species were identified.
  • the patient had tried numerous antibiotics, steroids, oral and topical anti-virals and anti-inflammatories without benefit.
  • Prepared was a composition as disclosed herein using 0.35% PVP-I in 45% DMSO with petralatum.
  • the patient was treated by applying the solution topically to the eye six times daily. Within three days improvement was noted in and around the eye.
  • the corneal melt had halted and re-epithelialization had taken place.
  • the hypopyon had resolved, the conjunctiva cleared and a small central infiltrate remained.
  • week two the patient was healed and no active bacterial infection remained.
  • a central corneal cicatrix was evident in the area of previous active infiltrate.
  • This patient was suffering from a bacterial corneal ulceration. In this type of infection there is often a history of contact lens use, however, this is not a prerequisite. Bacteria is introduced into the eye through a small break in the epithelium and gains foothold to the underlying structures. In this patient, the conjunctiva demonstrated diffuse injection with pyogenic discharge. The cornea demonstrated a central, five millimeter circular infiltrate with overlying central epithelial defect. The infiltrate had induced abundant stromalysis and the resultant cornea had thinned by approximately seventy five percent. There was a two millimeter layered hypopyon in the anterior chamber. Corneal cultures were taken, and Pseudomonas aeruginosa species was identified.
  • the patient had tried numerous antibiotics, steroids, oral and topical anti-virals and anti-inflammatories without benefit.
  • Prepared was a composition as disclosed herein using 0.2% PVP-I in 36% DMSO with polyvinylpyrrolidone.
  • the patient was treated by applying the solution topically to the eye six times daily. Within three days improvement was noted in and around the eye.
  • the corneal melt had halted and re-epithelialization had taken place.
  • the hypopyon had resolved, the conjunctiva cleared and a small central infiltrate remained.
  • week two the patient was healed and no active bacterial infection remained.
  • a central corneal cicatrix was evident in the area of previous active infiltrate.
  • This patient was suffering from a fungal corneal ulceration. In this type of infection there is often a history of contact lens use, however, this is not a prerequisite. Fungus is introduced into the eye through a small break in the epithelium and gains foothold to the underlying structures. In this patient, the conjunctiva demonstrated diffuse injection with pyogenic discharge.
  • the cornea contained multifocal, feather-like infiltrates with overlying central epithelial defect. The infiltrates had induced minimal stromalysis and the resultant cornea was not thinned. There was no hypopyon, however, cell and flare were present. Corneal cultures were taken, and Fusarium species was identified.
  • the patient had tried numerous antifungals, antibiotics, steroids, oral and topical anti-virals and anti-inflammatories without benefit.
  • Prepared was a composition as disclosed herein using 1.2% PVP-I in 45% DMSO with glycerin.
  • the patient was treated by applying the solution topically to the eye six times daily. Within one week improvement was noted in and around the eye.
  • the cornea had begun the process of re-epithelialization. At two weeks corneal infiltrate was resolved, the conjunctiva had cleared and the anterior chamber was quiet. A central corneal cicatrix was evident in the area of previous active infiltrate.
  • This patient was suffering from an Acanthamoeba corneal ulceration.
  • Acanthamoeba parasites are often introduced into the eye through a small break in the epithelium and gains foothold to the underlying structures.
  • the patient endorses pain out of proportion with examination.
  • the conjunctiva demonstrated diffuse injection.
  • the cornea contained multiple bullous lesions with enlarged corneal nerves.
  • This patient was suffering from conjunctival intraepithelial neoplasia.
  • conjunctiva In this type of dysplasia cells grow irregularly within the epithelium but do not break through the basement membrane. It is often associated with UV exposure, smoking, or human papilloma virus.
  • the conjunctiva demonstrated growth a fleshy limbal mass with leukoplakia. A prominent feeder vessel was present. The irregular area stained positively with rose bengal.
  • Conjunctival biopsy was taken and pathology report confirmed the diagnosis. The patient had tried numerous topical chemotherapeutic agents such as mitomycin and interferon. Eventual excision with cryotherapy was performed, however, the lesion recurred.
  • This patient was suffering from a conjunctival squamous cell carcinoma.
  • This type of dysplasia cells grow irregularly within the epithelium and break through the basement membrane into the conjunctival stroma. It is often associated with UV exposure, smoking, or human papilloma virus.
  • the conjunctiva demonstrated a fleshy limbal mass with leukoplakia. A prominent feeder vessel was present. The irregular area stained positively with rose bengal.
  • Conjunctival biopsy was taken and pathology report confirmed the diagnosis. The patient had tried numerous topical chemotherapeutic agents such as mitomycin and interferon. Eventual excision with cryotherapy was performed, however, the lesion recurred.
  • This patient was suffering from a corneal intraepithelial neoplasia.
  • This type of dysplasia cells grow irregularly within the corneal epithelium but do not break through the basement membrane. It is often associated with UV exposure, smoking, or human papilloma virus.
  • the cornea demonstrated a diffuse translucent gray growth with leukoplakia. The irregular area stained positively with rose bengal. Corneal biopsy was taken and pathology report confirmed the diagnosis. The patient had tried numerous topical chemotherapeutic agents such as mitomycin and interferon. Eventual excision with cryotherapy was performed, however, the lesion recurred.
  • This patient was suffering from a corneal squamous cell carcinoma.
  • This type of dysplasia cells grow irregularly within the corneal epithelium and break through the basement membrane to invade deeper structures. It is often associated with UV exposure, smoking, or human papilloma virus.
  • the cornea demonstrated a diffuse translucent gray growth with leukoplakia. The irregular area stained positively with rose bengal. Corneal biopsy was taken and pathology report confirmed the diagnosis. The patient had tried numerous topical chemotherapeutic agents such as mitomycin and interferon. Eventual excision with cryotherapy was performed, however, the lesion recurred.
  • Prepared was a composition as disclosed herein using 0.1% PVP-I in 30.5% DMSO with hydroxyethyl cellulose.
  • the patient was treated by applying the solution topically to the eye four times daily. Within one month improvement was noted in the eye. The corneal lesion had begun to involute and diminish in surface area. At two months there had been complete regression of the lesion with healthy appearing cornea. Post-treatment biopsy in the affected area was negative.
  • This patient was suffering from a conjunctival papilloma.
  • conjunctival cells demonstrate an exophytic or cauliflower-like pattern. They may also grow in a finger-like pattern and are often lobulated with vascular cores. The process is often associated with UV exposure, smoking, or human papilloma virus.
  • the conjunctiva demonstrated an exophytic mass with a pedunculated base, frond-like growth and vascular core.
  • Conjunctival biopsy was taken and pathology report confirmed the diagnosis. The patient had tried numerous topical chemotherapeutic agents such as mitomycin and interferon. Topical anti-inflammatories were also administered.
  • This patient was suffering from a corneal squamous papilloma.
  • corneal cells demonstrate an exophytic or cauliflower-like pattern. They may also grow in a finger-like pattern and are often lobulated with vascular cores. The process is often associated with UV exposure, smoking, or human papilloma virus.
  • the cornea demonstrated an exophytic mass with a pedunculated base, frond-like growth and vascular core. Corneal biopsy was taken and pathology report confirmed the diagnosis. The patient had tried numerous topical chemotherapeutic agents such as mitomycin and interferon. Topical anti-inflammatories were also administered.
  • This patient was suffering from an eyelid squamous papilloma.
  • cells demonstrate an exophytic or cauliflower-like pattern. They may also grow in a finger-like pattern and are often lobulated with vascular cores. The process is often associated with UV exposure, smoking, or human papilloma virus.
  • the eyelid lamellae demonstrated an exophytic mass with a pedunculated base, frond-like growth and vascular core. Eyelid biopsy was taken and pathology report confirmed the diagnosis. The patient had tried numerous topical chemotherapeutic agents such as mitomycin and interferon. Topical anti-inflammatories were also administered.
  • This patient was suffering from an eyelid verrucae.
  • This type of eyelid growth usually commences with gray or tan papules that progress to hyperkeratotic lesions with a papillomatous surface. The process is often associated with human papilloma virus infection of the epithelial layers.
  • the superior eyelid demonstrated a solid white growth with a papillomatous surface.
  • Eyelid biopsy was taken and pathology report confirmed the diagnosis.
  • the patient had tried numerous topical agents without benefit.
  • Cryotherapy was eventually performed, however, the lesion recurred.
  • Prepared was a composition as disclosed herein using 0.1% PVP-I in 43% DMSO with polypropylene glycol. The patient was treated by applying the solution topically to the eyelid structures four times daily. Within two weeks improvement was noted. The lesion had begun to involute and diminish in surface area. At one month there had been complete regression of the lesion with healthy appearing eyelid tissues and skin.
  • This patient was suffering from an eyelid associated molluscum contagiosum.
  • This type of eyelid infection usually demonstrates flesh colored, dome-shaped pearly papules with a dimpled centers. The process is often associated with pox virus infection of the epithelial layers.
  • the upper eyelid and lid margin demonstrated multiple flesh colored papules with dimpled centers.
  • the patient had tried numerous topical agents without benefit including salicylic acid and imiquimod.
  • Cryotherapy with excision was eventually performed, however, the lesions recurred.
  • Prepared was a composition as disclosed herein using 0.9% PVP-I in 39% DMSO with hydroxyethyl cellulose. The patient was treated by applying the solution topically to the eyelid and margin structures four times daily. Within two weeks improvement was noted. The lesions had begun to involute and diminish in surface area. At one month there had been complete regression of the lesions with healthy appearing eyelid tissues and lamellae.
  • This patient was suffering from an anterior and posterior blepharitis prior to cataract surgery. Numerous ophthalmic studies have implicated bacteria that populate the eyelids and conjunctiva as those being responsible for post-operative infectious endophthalmitis. It is therefore routine to attempt to sterilize these surfaces prior to commencing said procedure.
  • the posterior lid margin demonstrated meibomian gland thickening, keratinization, fat saponification, and dilated, telangectatic lid vessels.
  • the anterior lid margin also demonstrated scurf and bacterial overgrowth. The patient had tried numerous topical agents to sterilize the ocular surface including topical antibiotics and antiseptics without benefit.
  • This patient was suffering from an anterior and posterior blepharitis prior to intravitreal injection. Numerous ophthalmic studies have implicated bacteria that populate the eyelids and conjunctiva as those being responsible for post-injection infectious endophthalmitis. It is therefore routine to attempt to sterilize these surfaces prior to commencing said procedure.
  • the posterior lid margin demonstrated meibomian gland thickening, keratinization, fat saponification, and dilated, telangectatic lid vessels.
  • the anterior lid margin also demonstrated scurf and bacterial overgrowth. The patient had tried numerous topical agents to sterilize the ocular surface including topical antibiotics and antiseptics without benefit.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Reproductive Health (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US15/544,222 2015-01-20 2016-01-15 Iodophor composition and methods of use Expired - Fee Related US10314914B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/544,222 US10314914B2 (en) 2015-01-20 2016-01-15 Iodophor composition and methods of use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562105613P 2015-01-20 2015-01-20
US201562187973P 2015-07-02 2015-07-02
US15/544,222 US10314914B2 (en) 2015-01-20 2016-01-15 Iodophor composition and methods of use
PCT/US2016/013660 WO2016118424A1 (fr) 2015-01-20 2016-01-15 Nouvelle composition iodophore et procédés d'utilisation

Publications (2)

Publication Number Publication Date
US20180008715A1 US20180008715A1 (en) 2018-01-11
US10314914B2 true US10314914B2 (en) 2019-06-11

Family

ID=56417614

Family Applications (1)

Application Number Title Priority Date Filing Date
US15/544,222 Expired - Fee Related US10314914B2 (en) 2015-01-20 2016-01-15 Iodophor composition and methods of use

Country Status (12)

Country Link
US (1) US10314914B2 (fr)
EP (1) EP3247365A4 (fr)
JP (4) JP6280675B1 (fr)
KR (5) KR20190032629A (fr)
CN (2) CN111388408A (fr)
AU (1) AU2016209550A1 (fr)
BR (1) BR112017015387A2 (fr)
CA (1) CA2973725A1 (fr)
HK (1) HK1243354B (fr)
MX (1) MX2017009450A (fr)
PH (1) PH12017501300A1 (fr)
WO (1) WO2016118424A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110198720A (zh) * 2016-08-22 2019-09-03 维洛克生物制药有限责任公司 用于治疗哺乳动物中的疱疹病毒的组合物和方法
JP6255134B1 (ja) * 2016-11-02 2017-12-27 ヴェローチェ・バイオファーマ・エルエルシー 耳炎の治療のための組成物および方法
EP3672572A4 (fr) * 2017-08-22 2021-01-06 Veloce BioPharma, LLC Nouvelle composition ophtalmique et méthodes d'utilisation
CN107375319B (zh) * 2017-08-31 2020-12-18 山东省农业科学院家禽研究所 一种宠物用无色碘消毒剂及其制备和使用方法
WO2019226699A1 (fr) * 2018-05-21 2019-11-28 Veloce Biopharma Llc Nouveaux agents pour le traitement de maladies de la peau
TW202203946A (zh) * 2020-03-31 2022-02-01 越南商泰明製藥股份有限公司 用於人或動物之慢性或急性之病毒感染症及/或敗血症之預防或治療的組成物
JP2021161105A (ja) * 2020-03-31 2021-10-11 タイ ミン ファーマシューティカルズ ジェイエスシー ヒト又は動物の慢性若しくは急性のウイルス感染症及び／又は敗血症の予防若しくは治療のための組成物
FR3122572A1 (fr) * 2021-05-07 2022-11-11 Nadine GRISLAIN Composition pharmaceutique bioadhésive comprenant du PVPI
US20230181625A1 (en) * 2021-12-14 2023-06-15 Harrow Ip, Llc Method and composition for treating infectious conjunctivitis

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3551554A (en) 1968-08-16 1970-12-29 Crown Zellerbach Corp Enhancing tissue penetration of physiologically active agents with dmso
US4652557A (en) 1984-05-14 1987-03-24 Clark Pharmaceutical Laboratories Ltd. Pharmaceutical solutions comprising dimethyl sulfoxide
GB2275191A (en) 1993-02-10 1994-08-24 Donald John Dear Use of tolnaftate and tolciclate in treatment of skin disorder
US5516808A (en) 1994-10-27 1996-05-14 Sawaya; Assad S. Topical cellulose pharmaceutical formulation
US6391879B1 (en) 1998-11-16 2002-05-21 Astan, Inc. Therapeutic anti-fungal nail preparation
US20030049320A1 (en) 2000-12-18 2003-03-13 Wockhardt Limited Novel in-situ forming controlled release microcarrier delivery system
US20060165747A1 (en) 2005-01-24 2006-07-27 David Rolf Antifungal composition, method and kit for topically treating onychomycosis
US7462362B2 (en) 2003-03-21 2008-12-09 Nexmed Holdings, Inc. Antifungal nail coat and method of use
US20090162301A1 (en) 2005-06-10 2009-06-25 Tarrand Jeffrey J Antiseptic Compositions
US20090263345A1 (en) 2008-01-28 2009-10-22 Foresight Biotherapeutics, Inc. Otic compositions for the treatment of infections of the internal and external ear in mammals
WO2009151619A1 (fr) 2008-06-12 2009-12-17 Foresight Biotherapeutics, Inc. La povidone iodée, nouveau conservateur innovant pour compositions ophtalmiques
US20110217260A1 (en) 2010-03-04 2011-09-08 Shantha Totada R Method of enhancing eyelash and eye brow hair growth
WO2012154740A1 (fr) 2011-05-11 2012-11-15 Pellexa Research, Llc Compositions antifongiques pour le traitement de la peau et des ongles
US9770466B2 (en) * 2015-07-02 2017-09-26 Veloce Biopharma, Llc Ophthalmic composition and methods of use

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0410348A1 (fr) * 1989-07-26 1991-01-30 G.D. Searle & Co. Composition de spironolactone à usage topique
JP3583166B2 (ja) * 1994-06-27 2004-10-27 興和株式会社 損傷皮膚修復用粉末製剤
JP4116687B2 (ja) * 1997-12-05 2008-07-09 興和株式会社 損傷皮膚修復用半固形製剤
ATE330631T1 (de) * 1999-01-05 2006-07-15 Univ Southern Australia Antikörperfragmente zur lokalen behandlung von augenerkrankungen
ES2363729T3 (es) * 2001-04-27 2011-08-12 The General Hospital Corporation Diagnóstico ocular de la enfermedad de alzheimer.
ES2212907B1 (es) * 2003-01-20 2005-12-16 Luis Ignacio Olcina Portilla Preparados oftalmologicos a base de povidona yodada.
EP1449533A1 (fr) * 2003-02-24 2004-08-25 Euro-Celtique S.A. Utilisation d'iode PVP pour le traitement de l'acné
EP1449520A1 (fr) * 2003-02-24 2004-08-25 Euro-Celtique S.A. Utilisation d'iode PVP pour le traitement de l'herpes
EP1887864B1 (fr) * 2005-05-16 2020-02-12 Novapharm Research (Australia) Pty. Limited Composition pour preparer un patient a une intervention chirurgicale
US7767217B2 (en) 2006-03-14 2010-08-03 Foresight Biotherapeutics Ophthalmic compositions comprising povidone-iodine
US20110319805A1 (en) * 2010-06-29 2011-12-29 Bryan Knicely Morris Topical composition for treating the skin
US20120156202A1 (en) * 2010-11-05 2012-06-21 Shantha Totada R Age related macular degeneration treatment
WO2013122637A1 (fr) * 2012-02-17 2013-08-22 Capriotti Joseph Compositions antifongiques destinées au traitement de la peau et des ongles
US20140271529A1 (en) * 2013-03-14 2014-09-18 Alc Therapeutics, Llc Antifungal compositions for the treatment of secondary skin and nail infections

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3551554A (en) 1968-08-16 1970-12-29 Crown Zellerbach Corp Enhancing tissue penetration of physiologically active agents with dmso
US4652557A (en) 1984-05-14 1987-03-24 Clark Pharmaceutical Laboratories Ltd. Pharmaceutical solutions comprising dimethyl sulfoxide
GB2275191A (en) 1993-02-10 1994-08-24 Donald John Dear Use of tolnaftate and tolciclate in treatment of skin disorder
US5516808A (en) 1994-10-27 1996-05-14 Sawaya; Assad S. Topical cellulose pharmaceutical formulation
US6391879B1 (en) 1998-11-16 2002-05-21 Astan, Inc. Therapeutic anti-fungal nail preparation
US20030049320A1 (en) 2000-12-18 2003-03-13 Wockhardt Limited Novel in-situ forming controlled release microcarrier delivery system
US7462362B2 (en) 2003-03-21 2008-12-09 Nexmed Holdings, Inc. Antifungal nail coat and method of use
US20060165747A1 (en) 2005-01-24 2006-07-27 David Rolf Antifungal composition, method and kit for topically treating onychomycosis
US20090162301A1 (en) 2005-06-10 2009-06-25 Tarrand Jeffrey J Antiseptic Compositions
US8512724B2 (en) 2005-06-10 2013-08-20 The Board Of Regents Of The University Of Texas System Antiseptic compositions
US20090263345A1 (en) 2008-01-28 2009-10-22 Foresight Biotherapeutics, Inc. Otic compositions for the treatment of infections of the internal and external ear in mammals
US20120003174A1 (en) 2008-01-28 2012-01-05 Foresight Biotherapeutics, Inc. Otic compositions for the treatment of infections of the internal and external ear in mammals
US20130089510A1 (en) 2008-01-28 2013-04-11 Foresight Biotherapeutics, Inc. Otic compositions for the treatment of infections of the internal and external ear in mammals
WO2009151619A1 (fr) 2008-06-12 2009-12-17 Foresight Biotherapeutics, Inc. La povidone iodée, nouveau conservateur innovant pour compositions ophtalmiques
US20110217260A1 (en) 2010-03-04 2011-09-08 Shantha Totada R Method of enhancing eyelash and eye brow hair growth
WO2012154740A1 (fr) 2011-05-11 2012-11-15 Pellexa Research, Llc Compositions antifongiques pour le traitement de la peau et des ongles
US9770466B2 (en) * 2015-07-02 2017-09-26 Veloce Biopharma, Llc Ophthalmic composition and methods of use

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
Berkelman, Ruth, et al., Journal of Clinical Microbiology, Apr. 1982, p. 635-639 vol. 15, No. 4.
International Preliminary Report on Patentability (IPRP) in PCT/US2016/013660.
International Search Report and IPRP/Written Opinion in PCT/US2012/065298.
International Search Report in PCT/US2012/036942.
International Search Report in PCT/US2014/025470.
K. Capriotti and J. Capriotti, Chemotherapy-associated paronychia treated with a dilute povidone-iodine/dimethyl sulfoxide preparation, Clin. Cosmetic and Investigational Dermatology 2015:8 pp. 489-491.
K. Capriotti, et al., A Novel Topical 2% Povidone-Iodine Solution for the Treatment of Common Warts: A Randomized, Double-blind, Vehicle-Controlled Trial, Dermatol Ther., Nov. 3, 2015 (DOI 10.1007/s13555-015-0086-1) (open access at Springerlink.com).
K. Capriotti, et al., Molluscum Contagiosum Viral Infention Treated With a Dilute Povidone-Iodine/Dimethylsulfoxide Prepartion, Derm Ther. Dec. 21, 2015 (DOI 10.1007/s13555-015-0091-4) (open access at Springerlink.com).

Also Published As

Publication number Publication date
KR101961360B1 (ko) 2019-03-25
JP2018076364A (ja) 2018-05-17
KR20180011882A (ko) 2018-02-02
EP3247365A1 (fr) 2017-11-29
JP2018109046A (ja) 2018-07-12
KR20170126871A (ko) 2017-11-20
CN107405360B (zh) 2019-08-27
JP6307202B1 (ja) 2018-04-04
KR20190032629A (ko) 2019-03-27
AU2016209550A1 (en) 2017-08-03
JP6280675B1 (ja) 2018-02-14
JP2018065852A (ja) 2018-04-26
CA2973725A1 (fr) 2016-07-28
US20180008715A1 (en) 2018-01-11
MX2017009450A (es) 2018-01-18
BR112017015387A2 (pt) 2018-01-16
KR20180011883A (ko) 2018-02-02
HK1243354B (zh) 2020-05-08
CN107405360A (zh) 2017-11-28
WO2016118424A1 (fr) 2016-07-28
JP6359217B2 (ja) 2018-07-18
PH12017501300A1 (en) 2018-02-05
JP2018506577A (ja) 2018-03-08
EP3247365A4 (fr) 2018-08-01
KR20190031596A (ko) 2019-03-26
CN111388408A (zh) 2020-07-10

Similar Documents

Publication Publication Date Title
US10314914B2 (en) Iodophor composition and methods of use
US10398725B2 (en) Ophthalmic compositions and methods of use
HK1243354A1 (en) Novel iodophor composition and methods of use
US11738043B2 (en) Sodium chlorite compositions with enhanced antimicrobial efficacy and reduced toxicity
EP2316420A1 (fr) Procédé pour réduire la douleur
KR101934767B1 (ko) 신규한 안과용 조성물 및 사용 방법
WO2019135779A1 (fr) Nouvelle composition ophtalmique et méthodes d'utilisation
JP2004203836A (ja) 眼科用局所適用製剤
US20190060224A1 (en) Novel ophthalmic composition and methods of use
HK40024783A (en) Novel iodophor composition and methods of use
CA3169401A1 (fr) Formulations topiques ophtalmiques a base de xanthane ayant un regime posologique reduit
US20180200289A1 (en) Novel ophthalmic composition and methods of use
HK40004464A (en) Novel ophthalmic composition and methods of use
WO2019040051A1 (fr) Nouvelle composition ophtalmique et méthodes d'utilisation
US20190060355A1 (en) Novel ophthalmic composition and methods of use
US20210213045A1 (en) Novel ophthalmic composition and methods of use
CN1389206A (zh) 一种抗白内障眼药和角膜渗透促进剂氮酮的眼科应用
EA041271B1 (ru) Противозачаточная микробицидная композиция и способ предупреждения заболеваний, передающихся половым путем

Legal Events

Date Code Title Description
AS Assignment

Owner name: VELOCE BIOPHARMA, LLC, FLORIDA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CAPRIOTTI, KARA;REEL/FRAME:043025/0389

Effective date: 20160108

Owner name: VELOCE BIOPHARMA, LLC, FLORIDA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PELLETIER, JESSE;REEL/FRAME:043025/0429

Effective date: 20160108

Owner name: VELOCE BIOPHARMA, LLC, FLORIDA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CAPRIOTTI, JOSEPH;REEL/FRAME:043025/0356

Effective date: 20160108

AS Assignment

Owner name: VELOCE BIOPHARMA, LLC, FLORIDA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:STEWART, KEVIN;REEL/FRAME:043232/0580

Effective date: 20160108

STPP Information on status: patent application and granting procedure in general

Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS

STPP Information on status: patent application and granting procedure in general

Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20230611